The development and fabrication of plasmonics-active metallic nanostructures have been active areas of research for a wide variety of applications. Plasmonics refers to the study of enhanced electromagnetic properties of metallic nanostructures. The term is derived from plasmons, the quanta associated with longitudinal waves propagating in matter through the collective motion of large numbers of electrons. According to classical electromagnetic theory, molecules on or near metal nanostructures experience enhanced fields relative to that of the incident radiation. When a metallic nanostructured surface is irradiated by an incident electromagnetic field (e.g., a laser beam), conduction electrons are displaced into frequency oscillations equal to those of the incident light. These oscillating electrons, called “surface plasmons,” produce a secondary electric field, which adds to the incident field. The origin of plasmon resonances of metallic nanoparticles is collective oscillations of the conduction band electrons in the nanoparticles, which are called Localized Surface Plasmons (LSPs). LSPs can be excited when light is incident on metallic nanoparticles having a size much smaller than the wavelength of the incident light. At a suitable wavelength, resonant dipolar and multipolar modes can be excited in the nanoparticles, which lead to a significant enhancement in absorbed and scattered light and enhancement of electromagnetic fields inside and near the particles. Hence, the LSPs can be detected as resonance peaks in the absorption or scattering spectra of the metallic nanoparticles. This condition yields intense localized fields, which can interact with molecules in contact with or near the metal surface. In an effect analogous to a “lightning rod” effect, secondary fields can become concentrated at high curvature points on the nanostructured metal surface.
Nanoparticles of noble metals such as gold and silver resonantly scatter and absorb light in the visible and near-infrared spectral region upon the excitation of their plasmon and are therefore materials of choice for plasmon related devices. Surface plasmons have been associated with important practical applications in surface plasmon resonance (SPR), surface-enhanced Raman scattering (SERS) and surface-enhanced luminescence, also referred to as metal-enhanced luminescence. Such SERS technology has been extensively investigated and a wide variety of plasmonics-active SERS platforms developed for chemical sensing and for bioanalysis and biosensing [T. Vo-Dinh, “Surface-Enhanced Raman Spectroscopy Using Metallic Nanostructures,” Trends in Anal. Chem., 17, 557-582 (1998); T. Vo-Dinh, A. Dhawan, S. J. Norton, C. G. Khoury, H-N. Wang, V. Misra, and M. Gerhold “Plasmonic Nanoparticles and Nanowires: Design, Fabrication and Application in Sensing”, J. Phys. Chem. C, 114 (16), pp 7480-7488 (2010).
Photodynamic Therapy (PDT) is light-based treatment, which involves treatment of diseases such as cancer using light action on a special photoactive class of drugs, by photodynamic action in vivo to destroy or modify tissue [Dougherty T. J. and Levy J. G., “Photodynamic Therapy and Clinical Applications”, in Biomedical Photonics Handbook, Vo-Dinh T., Ed., CRC Press, Boca Raton Fla. (2003)]. PDT, which was originally developed for treatment of various cancers, has now been used to include treatment of pre-cancerous conditions, e.g. actinic keratoses, high-grade dysplasia in Barrett's esophagus, and non-cancerous conditions, e.g. various eye diseases, e.g. age related macular degeneration. Photodynamic therapy (PDT) is approved for commercialization worldwide both for various cancers (lung, esophagus) and for AMD. The PDT process requires three elements: (1) photosensitizer), (2) light that can excite the photosensitizer (Ps) and (3) endogenous oxygen. The putative cytotoxic agent is singlet oxygen, an electronically excited state of ground state triplet oxygen formed according to Type II photochemical process.
Transition to the triplet state is important since the triplet state has a relatively long lifetime (μsec to seconds). As a result photosensitizers that undergo efficient intersystem crossing to the excited triplet state will have sufficient time for collision with oxygen in order to produce singlet oxygen. The energy difference between ground state and singlet oxygen is 94.2 kJ/mol and corresponds to a transition in the near-infrared (NIR) at ˜1270 nm. Most PS photosensitizers in clinical use have triplet quantum yields in the range of 40-60% with the singlet oxygen yield being slightly lower. Competing processes include loss of energy by deactivation to ground state by fluorescence or internal conversion (loss of energy to the environment).
Many factors, including a high yield of singlet oxygen, pharmacokinetics, pharmacodynamics, stability in vivo and acceptable toxicity, play critical roles as well [Henderson B W, Gollnick S O, “Mechanistic Principles of Photodynamic Therapy”, in Biomedical Photonics Handbook, Vo-Dinh T., Ed., CRC Press, Boca Raton Fla. (2003)]. For example, it is desirable to have relatively selective uptake in the tumor or other tissue being treated relative to the normal tissue that necessarily will be exposed to the exciting light as well. Pharmacodynamic issues such as the subcellular localization of the photosensitizer may be important as certain organelles appear to be more sensitive to PDT damage than others (e.g. the mitochondria). Toxicity can become an issue if high doses of photosensitizer are necessary in order to obtain a complete response to treatment. An important mechanism associated with PDT drug activity involves apoptosis in cells. Upon absorption of light, the photosensitiser (Ps) initiates chemical reactions that lead to the direct or indirect production of cytotoxic species such as radicals and singlet oxygen. The reaction of the cytotoxic species with subcellular organelles and macromolecules (proteins, DNA, etc) lead to apoptosis and/or necrosis of the cells hosting the PDT drug. The preferential accumulation of PDT drug molecules in cancer cells combined with the localized delivery of light to the tumor, results in the selective destruction of the cancerous lesion. Compared to other traditional anticancer therapies, PDT does not involve generalized destruction of healthy cells. In addition to direct cell killing, PDT can also act on the vasculature, reducing blood flow to the tumor causing its necrosis. In particular cases it can be used as a less invasive alternative to surgery.
There are several chemical species used for PDT including porphyrin-based sensitizers. A purified hematoporphyrin derivative, Photofrin®, has received approval of the US Food and Drug Administration. Porphyrins are generally used for tumors on or just under the skin or on the lining of internal organs or cavities because theses drug molecules absorb light shorter than 640 nm in wavelength. For tumors occurring deep in tissue, second generation sensitizers, which have absorbance in the NIR region, such as porphyrin-based systems [R. K. Pandey, “Synthetic Strategies in designing Porphyrin-Based Photosensitizers”, in Biomedical Photonics Handbook, Vo-Dinh T., Ed., CRC Press, Boca Raton Fla. (2003)], chlorines, phthalocyanine, and naphthalocyanine have been investigated.
Nanoparticle systems have gained wide attention due to their potential in medicine, such as molecular imaging, immunization, theranostics, and targeted delivery/therapy. Nanoparticles can be fabricated as strong contrast agents for different imaging modalities with superior signal-to-noise ratios than conventional agents, or as therapeutic agents such as drug carriers, radioenhancers, and photothermal transducers. Gold nanoparticles (AuNPs), with their facile synthesis and biocompatibility, have therefore been applied for a variety of therapeutics, especially in cancer therapy.
These substrates consist of microplates, waveguides or optical fibers having silver-coated dielectric nanoparticles or isolated dielectric nanospheres coated with a silver nanolayer producing nanocaps (i.e. half nanoshells), nanorods and nanostars. These plasmonics substrate platforms have led to a wide variety of analytical applications including sensitive detection of a variety of chemicals of environmental, biological and medical significance, including polycyclic aromatic compounds, organophosphorus compounds, and compounds of biological interest such as DNA-adduct biomarkers.
Gold nanostars (NS), with a high absorption-to-scattering ratio in the NIR, efficiently transduce photon energy into heat for hyperthermia therapy. To date, most phothermolysis studies utilize laser irradiation higher than the maximal permissible exposure (MPE) of skin by ANSI regulation. To make photothermolysis applicable to real practice, one needs to enhance the photothermal transduction efficiency. One way is to use a pulsed laser instead of a continuous-wave laser, permitting efficient photothermal conversion by allowing additional time for electron-phonon relaxation. Previously, in vitro photothermolysis using NIR pulsed laser reported irradiances of 1.6-48.6 W/cm2; which were higher than the MPE of skin (e.g. 0.4 W/cm2 at 800 nm). Insufficient intracellular particle delivery and low photothermal transduction efficiency may be the main obstacles. Therefore, there is a strong need to design a more efficient photothermal transducer with optimized cellular uptake.
Recently, star-shaped AuNPs (“nanostars”) have attracted interest because their plasmon can be tuned to the NIR region, and the structure contains multiple sharp tips that can greatly enhance incident electromagnetic fields. Studies have shown that NIR-absorbing nanorods, nanocages or nanoshells can be used as contrast agents in optical imaging techniques such as optical coherent tomography, two-photon luminescence (TPL) microscopy, and photoacoustic imaging. Their large absorption cross-sections can also effectively convert photon energy to heat during photothermal therapy. Nanostars, which absorb in the NIR, have been hypothesized to behave similarly. Nanostar-related bioapplications remain scarce in spite of their potential, mostly due to the difficulty of surface functionalization.
In 2003, Chen et al. [Chen S, Wang Z L, BaHato J, Foulger S H, Carroll D L., J Am Chem Soc. 2003 Dec. 31; 125(52):16186-7] first reported the synthesis of multipod gold nanoparticles from silver plates in the presence of cetyltrimethylammonium bromide (CTAB) and NaOH. Later, several seedless or seed-mediated synthesis methods were employed using majorly poly(N-vinylpyrolidone) (PVP) or CTAB as surfactant. Further use of nanostars has been limited by (1) the potential toxicity of CTAB, (2) the difficulty of replacing PVP or CTAB during biofunctionalization, and (3) induction of aggregation following multiple washes. Previous experimental studies have shown a red-shifting of the plasmon peak from nanostars with longer or sharper branches. Several numerical studies of their plasmonic properties have recently been reported. Hao et al.'s [Hao F, Nehl C L, Hafner J H, Nordlander P. Nano Lett. 2007 March; 7(3):729-32] 2-D modeling of a single nanostar, consisting of 5 unique branches, with finite difference time domain (FDTD) method showed that nanostars plasmon results from the hybridization of plasmon resonance of each branch; the plasmon peak relative intensity depends on the polarization angle. Senthil et al. [Senthil Kumar P, Pastoriza-Santos I, Rodríguez-Ganzález B, Garcia de Abajo F J, Liz-Marzán L M. Nanotechnology, 2008; 19(1):015606-12] also stated that the tip angle and radius, but not the number of branches, are the major determining factors in plasmon shift in a simplistic 2-branch model.
Because existing nanoparticles are associated with limitations as described above, new nanoparticles with improved properties are therefore desirable.